Cardioprotective effects of rosiglitazone are associated with selective overexpression of type 2 angiotensin receptors and inhibition of p42/44 MAPK

Abstract

Molavi, Behzad, Jiawei Chen, and J. L. Mehta. Cardioprotective effects of rosiglitazone are associated with selective overexpression of type 2 angiotensin receptors and inhibition of p42/44 MAPK. Am J Physiol Heart Circ Physiol 291: H687-H693, 2006. First published March 31, 2006 doi:10.1152/ajpheart.00926.2005.-Current evidence points to renin-angiotensin system as a key mediator in ischemia-reperfusion injury. Rosiglitazone, a peroxisome proliferator-activated receptor-␥ (PPAR-␥) ligand, has recently been shown to confer cardioprotection against ischemia-reperfusion in animal models. We sought to examine the expression of ANG II receptors during PPAR-␥-mediated cardioprotection. Male Sprague-Dawley rats (nondiabetic) were fed either regular rat chow (control diet group, n ϭ 9) or rosiglitazone-rich diet (rosiglitazone-rich diet group, n ϭ 9) and were subjected to 1 h of myocardial ischemia followed by 1 h of reperfusion. A third group of rats had only thoracotomy and pericardiotomy and served as a sham control group (n ϭ 9). Hemodynamics, infarct size, and expression of ANG II type 1 and type 2 receptors (AT 1 and AT 2) were measured in all groups. There was a 58% reduction of infarct size in the rosiglitazone-rich diet group (P Ͻ 0.01 vs. control diet group). Increased myocardial expression of AT 1 receptors in the ischemic-reperfused myocardium was attenuated in the rosiglitazonerich diet group (P Ͻ 0.05 vs. control diet group). Importantly, myocardial AT 2 mRNA and protein expression were significantly increased (by Ͼ100-fold) in the rosiglitazone-rich diet group (P Ͻ 0.05). These changes were accompanied by inhibition of p42/44 MAPK in the rosiglitazone-rich diet group, while the Akt1 expression, believed to mediate insulin sensitization, remained similar in all three groups. The cardioprotective effects of rosiglitazone against myocardial ischemia-reperfusion injury are independent of its insulin-sensitizing properties and are associated with significant overexpression of AT 2 receptors along with inhibition of p42/44 MAPK. peroxisome proliferator-activated-␥ receptors; angiotensin receptors; ischemia-reperfusion injury; rosiglitazone THE IMPLEMENTATION of immediate reperfusion strategies to salvage the ischemic myocardium has reduced mortality and morbidity in the setting of acute coronary syndromes (8) but has also brought the phenomenon of ischemia-reperfusion injury into focus. This phenomenon can present clinically as acute congestive heart failure or malignant ventricular arrhythmias after successful revascularization.Previous studies have shown that ANG II type 1 (AT 1 ) receptors are overexpressed during ischemia-reperfusion and exert deleterious effects on myocardial contractility (37,38). Although a few studies have failed to show any cardioprotective effects by angiotensin receptor blockers, the bulk of current evidence suggests that AT 1 receptor blockade is associated with cardioprotection (28, 33). In addition, AT 1 receptor blockade during ischemia-reperfusion injury in rat hearts is assoc...

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